Identification of residues of SARS-CoV nsp1 that differentially affect inhibition of gene expression and antiviral signaling.
Identification of residues of SARS-CoV nsp1 that differentially affect inhibition of gene expression and antiviral signaling.
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DOI：
10.1371/journal.pone.0062416
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Wathelet MG
中科院分区：
文献类型：
--
作者：
Jauregui AR;Savalia D;Lowry VK;Farrell CM;Wathelet MG
严重急性呼吸道综合征（SARS）的流行导致了相关冠状病毒SARS-CoV的鉴定。该病毒部分通过其非结构蛋白（nsp）1的表达来逃避宿主先天免疫应答，该非结构蛋白1抑制宿主基因表达以及病毒和干扰素（IFN）依赖性信号传导。因此，nsp 1是一个有希望的药物靶点，因为抑制nsp 1将使SARS-CoV更容易受到宿主抗病毒防御的影响。为了更好地了解nsp 1的作用模式，我们产生并分析了38个SARS-CoV nsp 1突变体，靶向180个氨基酸蛋白中的62个溶剂暴露残基。从这项工作中，我们确定了六类突变体，消除，减弱或增加nsp 1抑制宿主基因表达和/或抗病毒信号。各类突变体聚集在SARS CoV nsp 1表面，表明nsp 1与不同的宿主因子相互作用，发挥其抑制活性。nsp 1残基的识别及其活动的关键和参与这些活动的途径应有助于设计针对nsp 1的药物。值得注意的是，几个点突变增加了nsp 1的抑制活性，表明冠状病毒可以通过这些残基的突变进化出更大的逃避宿主反应的能力。
An epidemic of Severe Acute Respiratory Syndrome (SARS) led to the identification of an associated coronavirus, SARS-CoV. This virus evades the host innate immune response in part through the expression of its non-structural protein (nsp) 1, which inhibits both host gene expression and virus- and interferon (IFN)-dependent signaling. Thus, nsp1 is a promising target for drugs, as inhibition of nsp1 would make SARS-CoV more susceptible to the host antiviral defenses. To gain a better understanding of nsp1 mode of action, we generated and analyzed 38 mutants of the SARS-CoV nsp1, targeting 62 solvent exposed residues out of the 180 amino acid protein. From this work, we identified six classes of mutants that abolished, attenuated or increased nsp1 inhibition of host gene expression and/or antiviral signaling. Each class of mutants clustered on SARS-CoV nsp1 surface and suggested nsp1 interacts with distinct host factors to exert its inhibitory activities. Identification of the nsp1 residues critical for its activities and the pathways involved in these activities should help in the design of drugs targeting nsp1. Significantly, several point mutants increased the inhibitory activity of nsp1, suggesting that coronaviruses could evolve a greater ability to evade the host response through mutations of such residues.
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DOI：
10.1038/nrmicro2147
发表时间：
2009-06
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.7
作者：
Haller O;Kochs G;Weber F
通讯作者：
Weber F
影响因子：
6.7
作者：
Huang C;Lokugamage KG;Rozovics JM;Narayanan K;Semler BL;Makino S
通讯作者：
Makino S
DOI：
10.1073/pnas.0603144103
发表时间：
2006-08-22
影响因子：
11.1
作者：
Kamitani, Wataru;Narayanan, Krishna;Makino, Shinji
通讯作者：
Makino, Shinji
影响因子：
1.6
作者：
Lu X;Pan J;Tao J;Guo D
通讯作者：
Guo D